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United States Patent | 6,086,896 |
Sparling ,   et al. | July 11, 2000 |
An isolated, antigenic polypeptide comprises a segment having at least fifty amino acid residues. The amino acid sequence of the segment is present in N. meningitidis, and is different from, but substantially homologous with, the amino acid sequence of a segment of a member of the hemolysin family of toxins.
Inventors: | Sparling; P. Frederick (Moncure, NC); Thompson; Stuart (Carrboro, NC) |
Assignee: | ImClone Systems Incorporated (New York, NY) |
Appl. No.: | 323477 |
Filed: | October 14, 1994 |
Current U.S. Class: | 424/250.1; 424/184.1; 424/185.1; 424/249.1; 435/7.1; 530/350 |
Intern'l Class: | A61K 039/095; A61K 039/02; C07K 014/22; G01N 033/53 |
Field of Search: | 424/250.1,184.1,185.1 530/350 435/69.1,69.3,7.1 |
5141743 | Aug., 1992 | Schryvers | 424/92. |
Foreign Patent Documents | |||
9203467 | Mar., 1992 | WO | . |
Schryvers et al, Inf & Imm 56:1144-1149, 1988," Identification & Characterization of the Human Lactoferrin-Binding Protein from Neisseria meningitidis". Conlon et al, Inf & Imm 59:587-591 1991, "Efficacy of Recombinant Leukotokin in Protection Against Pneumonic Challenge with Live Pasteurella Memolytic Al". Thompson et al Journ. of Bact 175:811-818, 1993, "Neisseria meningitidis Produces Iron-regulated Proteins Related to the RTX Family of Exoproteins". Black et al, Infect & Imm. 54:710-713 1986, Human Immune Response to Iron-Repersible Outer Membrane Protein of Neisseria meningitidis. Labo et al, (Abst of Gen. Meeting of ASM, p. 31 B-37, May 1991. Thompson et al (Abst of Gen Meeting of ASM p. 32, B-38, May 1991. Felmlee, Dis. Abstract vol. 49, p. 1535. Patterson, "Neisseria meningitides and Meningo Coccal Disease," in the Biologic and Clinical Basis of Infections Diseases, W.B. Saunders Company, Chapter 43 (1980). Brener et al, Infection and Immunity 33, 59-66, 1981. Welch et al, Infection and Immunity 42:178-186, 1986. Black et al, Infection and Immunity 54:710-713, 1986. Glaser, Molecular Biology 2:19-30, 1988. Kolodrubetz et al, Infection and Immunity 57:1465-1469, 1989. |
__________________________________________________________________________ # SEQUENCE LISTING - (1) GENERAL INFORMATION: - (iii) NUMBER OF SEQUENCES: 2 - (2) INFORMATION FOR SEQ ID NO:1: - (i) SEQUENCE CHARACTERISTICS: #pairs (A) LENGTH: 3758 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - (ii) MOLECULE TYPE: DNA (genomic) - (iii) HYPOTHETICAL: NO - (iv) ANTI-SENSE: NO - (v) FRAGMENT TYPE: N-terminal - (vi) ORIGINAL SOURCE: #meningitidis ORGANISM: Neisseria - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 298..3645 - (ix) FEATURE: (A) NAME/KEY: mat.sub.-- - #peptide (B) LOCATION: 298..3642 - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: - TATATGTCTT TATTTGAATA TATCTTACGA TGGGGAAATA TTTATATATT TT - #ATAATAAA 60 - TTTTACTCAT TTGCTAATAT GTCATGGAAT ATTACTTGTA TTTTGTAGAA TT - #TTTCCATA 120 - TGAAAATATT CCATTTACTA TTTTTCTGAA CTTTATTAGT TTATTTTTAA TA - #TTTTTACC 180 - TCTTATATTT ACCATAAGAG AGCTAATTGA TTCATATTAT ATTGAGTCGA TA - #ATTAATTT 240 - ATTCTTAATT TTAATTCCTC ACGTTATTTT TTTAATTTAC TTGAAAGGAA AG - #CAGAT 297 - ATG ACA TCT GCA AAT TTT AAT ATT AAC GGT TT - #T GGA GAT GTG AAA TTA 345 Met Thr Ser Ala Asn Phe Asn Ile Asn Gly Ph - #e Gly Asp Val Lys Leu # 15 - ACA CCC TAT TCA CCA CTC TTG GGA TAT AAA GC - #T TGG GAT TCA TTT ATT 393 Thr Pro Tyr Ser Pro Leu Leu Gly Tyr Lys Al - #a Trp Asp Ser Phe Ile # 30 - GGT TCT ATT CAA TCC TTA TCT GAT TTA ATC TA - #T AAT GTG GAT AAC AAT 441 Gly Ser Ile Gln Ser Leu Ser Asp Leu Ile Ty - #r Asn Val Asp Asn Asn # 45 - AGA AAT AAA ATG GAA ATT ACT GTT AAT AAT GC - #T ATC CAA GCT GCA GAT 489 Arg Asn Lys Met Glu Ile Thr Val Asn Asn Al - #a Ile Gln Ala Ala Asp # 60 - AGC TTT TTA AGC AGT ATT GGA AGA GAT AAC AA - #A ATA ACA AAT ACT GCT 537 Ser Phe Leu Ser Ser Ile Gly Arg Asp Asn Ly - #s Ile Thr Asn Thr Ala # 80 - TCT TTA CTT GCA TCC CTC GAT AAC ATT TTT TT - #A AAT TTA AGA AAT GTA 585 Ser Leu Leu Ala Ser Leu Asp Asn Ile Phe Le - #u Asn Leu Arg Asn Val # 95 - TCT CGA GAT ATA CGA GAA ACA GGA AAA TTT AA - #A CCT AAT GAT ATT CAA 633 Ser Arg Asp Ile Arg Glu Thr Gly Lys Phe Ly - #s Pro Asn Asp Ile Gln # 110 - CAA GCA ATT GGT GAT ATA TTC ATT GCT GCT GG - #T GAT GGA TTA CAA TAT 681 Gln Ala Ile Gly Asp Ile Phe Ile Ala Ala Gl - #y Asp Gly Leu Gln Tyr # 125 - ATA AAA CAA CAA ACA GAG GCG ATG GCT CAA AG - #C AAA TTC TTA CCA ACT 729 Ile Lys Gln Gln Thr Glu Ala Met Ala Gln Se - #r Lys Phe Leu Pro Thr # 140 - AAA TTA AAA ACT GGT TTA AAT GAT GTC CTT AA - #T TCT AGA ATG CTA AAA 777 Lys Leu Lys Thr Gly Leu Asn Asp Val Leu As - #n Ser Arg Met Leu Lys 145 1 - #50 1 - #55 1 - #60 - TCC TCT ACT GTT TTA CAG CAT GAA TTG AAT TA - #T TTG GGA TTT AAA ATA 825 Ser Ser Thr Val Leu Gln His Glu Leu Asn Ty - #r Leu Gly Phe Lys Ile # 175 - AAG GAT TAT GGA AAC GAG AGG CTT GGC GAA TC - #T ATA ATG AAT ATA GAT 873 Lys Asp Tyr Gly Asn Glu Arg Leu Gly Glu Se - #r Ile Met Asn Ile Asp # 190 - GAT TTT ACA CCA AGT AAG ATA GCA AAC TTT TT - #T GCG GAT CCT GAT ACA 921 Asp Phe Thr Pro Ser Lys Ile Ala Asn Phe Ph - #e Ala Asp Pro Asp Thr # 205 - TAC AGC AAT GTA TTA GAA GAA GTA TCT AGG TT - #T ATA TAT TCC TTA GTT 969 Tyr Ser Asn Val Leu Glu Glu Val Ser Arg Ph - #e Ile Tyr Ser Leu Val # 220 - CCT GAT GAT GCA AAC CCT TGG AAA GGG GGC GA - #A GAT TAT ATT GGA CGA 1017 Pro Asp Asp Ala Asn Pro Trp Lys Gly Gly Gl - #u Asp Tyr Ile Gly Arg 225 2 - #30 2 - #35 2 - #40 - GGG ATA AGT GAA TGG GGA GAG TTA CTG GAA AA - #A TGG TAT AAA CAA GAT 1065 Gly Ile Ser Glu Trp Gly Glu Leu Leu Glu Ly - #s Trp Tyr Lys Gln Asp # 255 - TTT CTC CCT TAT CTT GAA AAA GAA TGG GAC CA - #A TTT CCG AAA TTT GAA 1113 Phe Leu Pro Tyr Leu Glu Lys Glu Trp Asp Gl - #n Phe Pro Lys Phe Glu # 270 - GAT TGG CTG CCT GAA TTC CCT GAA TGG GCA AG - #A GAG TGG TTG AAA TTA 1161 Asp Trp Leu Pro Glu Phe Pro Glu Trp Ala Ar - #g Glu Trp Leu Lys Leu # 285 - GAT CCC AAA CGT TCA GGC AAA TAT CAT GTC TA - #C GAC CCC CTC GCC CTA 1209 Asp Pro Lys Arg Ser Gly Lys Tyr His Val Ty - #r Asp Pro Leu Ala Leu # 300 - GAT CTA GAC GGC GAC GGT ATA GAA ACC GTT GC - #T GCC AAA GGC TTT GCA 1257 Asp Leu Asp Gly Asp Gly Ile Glu Thr Val Al - #a Ala Lys Gly Phe Ala 305 3 - #10 3 - #15 3 - #20 - GGT GCA TTG TTC GAC CAC CGC AAT CAA GGC AT - #C CGC ACC GCC ACC GGT 1305 Gly Ala Leu Phe Asp His Arg Asn Gln Gly Il - #e Arg Thr Ala Thr Gly # 335 - TGG GTT TCT GCC GAT GAC GGT TTA CTC GTC CG - #C GAT TTG AAC GGC AAC 1353 Trp Val Ser Ala Asp Asp Gly Leu Leu Val Ar - #g Asp Leu Asn Gly Asn # 350 - GGC ATC ATC GAC AAC GGC GCG GAA CTC TTC GG - #C GAC AAC ACC AAA CTG 1401 Gly Ile Ile Asp Asn Gly Ala Glu Leu Phe Gl - #y Asp Asn Thr Lys Leu # 365 - GCA GAC GGT TCT TTT GCC AAA CAC GGC TAT GC - #A GCT TTG GCC GAA TTG 1449 Ala Asp Gly Ser Phe Ala Lys His Gly Tyr Al - #a Ala Leu Ala Glu Leu # 380 - GAT TCA AAC GGC GAC AAC ATC ATC AAC GCG GC - #A GAC GCC GCA TTC CAA 1497 Asp Ser Asn Gly Asp Asn Ile Ile Asn Ala Al - #a Asp Ala Ala Phe Gln 385 3 - #90 3 - #95 4 - #00 - ACC CTG CGT GTA TGG CAG GAT CTC AAC CAG GA - #C GGC ATT TCC CAA GCT 1545 Thr Leu Arg Val Trp Gln Asp Leu Asn Gln As - #p Gly Ile Ser Gln Ala # 415 - AAT GAA TTG CGT ACC CTT GAA GAA TTG GGT AT - #C CAA TCT TTG GAT CTC 1593 Asn Glu Leu Arg Thr Leu Glu Glu Leu Gly Il - #e Gln Ser Leu Asp Leu # 430 - GCC TAT AAA GAT GTA AAT AAA AAT CTC GGT AA - #C GGT AAC ACT TTG GCT 1641 Ala Tyr Lys Asp Val Asn Lys Asn Leu Gly As - #n Gly Asn Thr Leu Ala # 445 - CAG CAA GGC AGC TAT ACC AAA ACA GAC GGT AC - #A ACC GCA AAA ATG GGG 1689 Gln Gln Gly Ser Tyr Thr Lys Thr Asp Gly Th - #r Thr Ala Lys Met Gly # 460 - GAT TTA CTT TTA GCA GCC GAC AAT CTG CAC AG - #C CGC TTC AAA GAC AAA 1737 Asp Leu Leu Leu Ala Ala Asp Asn Leu His Se - #r Arg Phe Lys Asp Lys 465 4 - #70 4 - #75 4 - #80 - GTG GAA CTC ACT GCC GAA CAG GCA AAA GCC GC - #C AAT CTT GCG GGC ATC 1785 Val Glu Leu Thr Ala Glu Gln Ala Lys Ala Al - #a Asn Leu Ala Gly Ile # 495 - GGC CGT CTG CGC GAT TTG CGC GAA GCT GCC GC - #A TTG TCC GGC GAT TTG 1833 Gly Arg Leu Arg Asp Leu Arg Glu Ala Ala Al - #a Leu Ser Gly Asp Leu # 510 - GCC AAT ATG CTG AAA GCT TAT TCT GCC GCC GA - #A ACT AAA GAA GCA CAG 1881 Ala Asn Met Leu Lys Ala Tyr Ser Ala Ala Gl - #u Thr Lys Glu Ala Gln # 525 - TTG GCA TTG TTA GAT AAT TTG ATT CAC AAA TG - #G GCG GAA ACC GAT TCG 1929 Leu Ala Leu Leu Asp Asn Leu Ile His Lys Tr - #p Ala Glu Thr Asp Ser # 540 - AAC TGG GGC AAA AAA TCG CCA ATG CGA CTT TC - #A ACC GAT TGG ACG CAA 1977 Asn Trp Gly Lys Lys Ser Pro Met Arg Leu Se - #r Thr Asp Trp Thr Gln 545 5 - #50 5 - #55 5 - #60 - ACG GCT AAT GAA GGT ATT GCA CTG ACA CCA TC - #C CAA GTA GCA CAA CTA 2025 Thr Ala Asn Glu Gly Ile Ala Leu Thr Pro Se - #r Gln Val Ala Gln Leu # 575 - AAA AAG AAC GCT TTA GTT TCC CTT TCT GAT AA - #A GCT AAA GCA GCT ATT 2073 Lys Lys Asn Ala Leu Val Ser Leu Ser Asp Ly - #s Ala Lys Ala Ala Ile # 590 - GAC GCC GCC CGC GAC CGC ATT GCC GTG CTT GA - #T GCC TAC ACG GGG CAG 2121 Asp Ala Ala Arg Asp Arg Ile Ala Val Leu As - #p Ala Tyr Thr Gly Gln # 605 - GAT TCC AGC ACA CTC TAT TAC ATG AGC GAA GA - #A GAC GCG CTT AAT ATC 2169 Asp Ser Ser Thr Leu Tyr Tyr Met Ser Glu Gl - #u Asp Ala Leu Asn Ile # 620 - GTC AAA GTA ACC AAC GAT ACA TAC GAC CAT CT - #C GCC AAA AAC ATC TAC 2217 Val Lys Val Thr Asn Asp Thr Tyr Asp His Le - #u Ala Lys Asn Ile Tyr 625 6 - #30 6 - #35 6 - #40 - CAA AAC CTG TTG TTC CAA ACC CGT TTG CAG CC - #A TAT TTG AAT CAA ATC 2265 Gln Asn Leu Leu Phe Gln Thr Arg Leu Gln Pr - #o Tyr Leu Asn Gln Ile # 655 - AGT TTC AAA ATG GAA AAT GAT ACG TTC ACT TT - #G GAT TTT AGT GGT CTT 2313 Ser Phe Lys Met Glu Asn Asp Thr Phe Thr Le - #u Asp Phe Ser Gly Leu # 670 - GTT CAA GCA TTT AAC CAT GTC AAA GAA ACT AA - #T CCG CAA AAA GCT TTT 2361 Val Gln Ala Phe Asn His Val Lys Glu Thr As - #n Pro Gln Lys Ala Phe # 685 - GTG GAT TTG GCC GAG ATG CTT GCA TAT GGC GA - #A CTT CGT TCT TGG TAT 2409 Val Asp Leu Ala Glu Met Leu Ala Tyr Gly Gl - #u Leu Arg Ser Trp Tyr # 700 - GAA GGC CGA AGA CTA ATG GCC GAT TAT GTG GA - #G GAG GCA AAA AAA GCA 2457 Glu Gly Arg Arg Leu Met Ala Asp Tyr Val Gl - #u Glu Ala Lys Lys Ala 705 7 - #10 7 - #15 7 - #20 - GGT AAA TTT GAA GAT TAC CAG AAA GTG TTG GG - #T CAG GAG ACC GTT GCA 2505 Gly Lys Phe Glu Asp Tyr Gln Lys Val Leu Gl - #y Gln Glu Thr Val Ala # 735 - TTA TTA GCT AAA ACA TCG GGT ACG CAA GCA GA - #T GAT ATC CTG CAA AAT 2553 Leu Leu Ala Lys Thr Ser Gly Thr Gln Ala As - #p Asp Ile Leu Gln Asn # 750 - GTA GGC TTT GGT CAT AAT AAA AAT GTT TCT TT - #A TAT GGT AAT GAC GGC 2601 Val Gly Phe Gly His Asn Lys Asn Val Ser Le - #u Tyr Gly Asn Asp Gly # 765 - AAC GAC ACT CTA ATC GGC GGT GCA GGC AAT GA - #T TAC TTG GAG GGC GGC 2649 Asn Asp Thr Leu Ile Gly Gly Ala Gly Asn As - #p Tyr Leu Glu Gly Gly # 780 - AGC GGT TCG GAT ACT TAT GTC TTC GGC AAA GG - #C TTC GGT CAG GAT ACG 2697 Ser Gly Ser Asp Thr Tyr Val Phe Gly Lys Gl - #y Phe Gly Gln Asp Thr 785 7 - #90 7 - #95 8 - #00 - GTC TAT AAT TAC GAC TAC GCT ACC GGA CGC AA - #A GAC ATC ATC CGC TTT 2745 Val Tyr Asn Tyr Asp Tyr Ala Thr Gly Arg Ly - #s Asp Ile Ile Arg Phe # 815 - ACC GAC GGT ATT ACA GCC GAT ATG CTG ACT TT - #T ACC CGA GAG GGC AAC 2793 Thr Asp Gly Ile Thr Ala Asp Met Leu Thr Ph - #e Thr Arg Glu Gly Asn # 830 - CAT CTT CTT ATC AAG GCA AAA GAC GAC AGT GG - #A CAA GTG ACT GTT CAG 2841 His Leu Leu Ile Lys Ala Lys Asp Asp Ser Gl - #y Gln Val Thr Val Gln # 845 - TCC TAT TTC CAG AAC GAT GGC TCA GGT GCT TA - #C CGT ATC GAT GAG ATT
2889 Ser Tyr Phe Gln Asn Asp Gly Ser Gly Ala Ty - #r Arg Ile Asp Glu Ile # 860 - CAT TTC GAT AAC GGC AAA GTA CTG GAT GTT GC - #C ACT GTC AAA GAA CTG 2937 His Phe Asp Asn Gly Lys Val Leu Asp Val Al - #a Thr Val Lys Glu Leu 865 8 - #70 8 - #75 8 - #80 - GTA CAG CAA TCC ACC GAC GGT TCG GAC AGA TT - #G TAT GCC TAC CAA TCC 2985 Val Gln Gln Ser Thr Asp Gly Ser Asp Arg Le - #u Tyr Ala Tyr Gln Ser # 895 - GGA AGT ACC TTA AAT GGC GGA TTG GGC GAT GA - #C TAT CTG TAC GGT GCC 3033 Gly Ser Thr Leu Asn Gly Gly Leu Gly Asp As - #p Tyr Leu Tyr Gly Ala # 910 - GAC GGG AAT GAC CTG CTG AAT GGT GAT GCA GG - #C AAC GAC AGT ATC TAC 3081 Asp Gly Asn Asp Leu Leu Asn Gly Asp Ala Gl - #y Asn Asp Ser Ile Tyr # 925 - AGT GGC AAT GGC AAT GAT ACG CTC GAT GGA GG - #A GAA GGC AAC GAC GCC 3129 Ser Gly Asn Gly Asn Asp Thr Leu Asp Gly Gl - #y Glu Gly Asn Asp Ala # 940 - CTG TAC GGC TAT AAT GGT AAC GAT GCA CTG AA - #T GGT GGC GAA GGC AAT 3177 Leu Tyr Gly Tyr Asn Gly Asn Asp Ala Leu As - #n Gly Gly Glu Gly Asn 945 9 - #50 9 - #55 9 - #60 - GAT CAT TTG AAC GGC GAA GAC GGT AAC GAC AC - #T CTA ATC GGC GGT GCA 3225 Asp His Leu Asn Gly Glu Asp Gly Asn Asp Th - #r Leu Ile Gly Gly Ala # 975 - GGC AAT GAT TAC TTG GAG GGC GGC AGC GGT TC - #G GAT ACT TAT GTC TTC 3273 Gly Asn Asp Tyr Leu Glu Gly Gly Ser Gly Se - #r Asp Thr Tyr Val Phe # 990 - GGC GAA GGC TTC GGT CAG GAT ACG GTC TAT AA - #T TAC CAT GTG GAT AAA 3321 Gly Glu Gly Phe Gly Gln Asp Thr Val Tyr As - #n Tyr His Val Asp Lys # 10050 - AAC TCT GAC ACT ATG CAC TTT AAA GGA TTT AA - #A GCA GCA GAT GTT CAT 3369 Asn Ser Asp Thr Met His Phe Lys Gly Phe Ly - #s Ala Ala Asp Val His # 10205 - TTT ATC CGT TCC GGA AGT GAT TTG GTG CTT AG - #C GCT TCT GAA CAA GAC 3417 Phe Ile Arg Ser Gly Ser Asp Leu Val Leu Se - #r Ala Ser Glu Gln Asp # 10401030 - # 1035 - AAC GTA CGT ATT TCC GGA TTC TTC TAT GGT GA - #A AAC CAT CGT GTA GAT 3465 Asn Val Arg Ile Ser Gly Phe Phe Tyr Gly Gl - #u Asn His Arg Val Asp # 10550 - ACA TTT GTC TTT GAT GAT GCA GCT ATC AGT AA - #T CCA GAT TTT GCC AAG 3513 Thr Phe Val Phe Asp Asp Ala Ala Ile Ser As - #n Pro Asp Phe Ala Lys # 10705 - TAT ATT AAT GCT GGC AAT AAT TTG GTA CAG TC - #T ATG TCT GTG TTC GGT 3561 Tyr Ile Asn Ala Gly Asn Asn Leu Val Gln Se - #r Met Ser Val Phe Gly # 10850 - TCT AAT ACT GCT GCG ACA GGA GGA AAT GTG GA - #T GCC AAT ATA CAA TCC 3609 Ser Asn Thr Ala Ala Thr Gly Gly Asn Val As - #p Ala Asn Ile Gln Ser # 11005 - GTA CAG CAG CCG TTA TTG GTA ACG CCA TCT GC - #A TAAGGAGCCT AATCACATTC 3662 Val Gln Gln Pro Leu Leu Val Thr Pro Ser Al - #a 1105 1110 - # 1115 - ATGGCTTAAA CTGAAAAACA GCAATCAAGT TTATTTTGAT TGCTGTTTTT CT - #TAATATTG 3722 # 3758 CTTT GCAAAAATAG TCTGTT - (2) INFORMATION FOR SEQ ID NO:2: - (i) SEQUENCE CHARACTERISTICS: #acids (A) LENGTH: 1115 amino (B) TYPE: amino acid (D) TOPOLOGY: linear - (ii) MOLECULE TYPE: protein - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: - Met Thr Ser Ala Asn Phe Asn Ile Asn Gly Ph - #e Gly Asp Val Lys Leu # 15 - Thr Pro Tyr Ser Pro Leu Leu Gly Tyr Lys Al - #a Trp Asp Ser Phe Ile # 30 - Gly Ser Ile Gln Ser Leu Ser Asp Leu Ile Ty - #r Asn Val Asp Asn Asn # 45 - Arg Asn Lys Met Glu Ile Thr Val Asn Asn Al - #a Ile Gln Ala Ala Asp # 60 - Ser Phe Leu Ser Ser Ile Gly Arg Asp Asn Ly - #s Ile Thr Asn Thr Ala # 80 - Ser Leu Leu Ala Ser Leu Asp Asn Ile Phe Le - #u Asn Leu Arg Asn Val # 95 - Ser Arg Asp Ile Arg Glu Thr Gly Lys Phe Ly - #s Pro Asn Asp Ile Gln # 110 - Gln Ala Ile Gly Asp Ile Phe Ile Ala Ala Gl - #y Asp Gly Leu Gln Tyr # 125 - Ile Lys Gln Gln Thr Glu Ala Met Ala Gln Se - #r Lys Phe Leu Pro Thr # 140 - Lys Leu Lys Thr Gly Leu Asn Asp Val Leu As - #n Ser Arg Met Leu Lys 145 1 - #50 1 - #55 1 - #60 - Ser Ser Thr Val Leu Gln His Glu Leu Asn Ty - #r Leu Gly Phe Lys Ile # 175 - Lys Asp Tyr Gly Asn Glu Arg Leu Gly Glu Se - #r Ile Met Asn Ile Asp # 190 - Asp Phe Thr Pro Ser Lys Ile Ala Asn Phe Ph - #e Ala Asp Pro Asp Thr # 205 - Tyr Ser Asn Val Leu Glu Glu Val Ser Arg Ph - #e Ile Tyr Ser Leu Val # 220 - Pro Asp Asp Ala Asn Pro Trp Lys Gly Gly Gl - #u Asp Tyr Ile Gly Arg 225 2 - #30 2 - #35 2 - #40 - Gly Ile Ser Glu Trp Gly Glu Leu Leu Glu Ly - #s Trp Tyr Lys Gln Asp # 255 - Phe Leu Pro Tyr Leu Glu Lys Glu Trp Asp Gl - #n Phe Pro Lys Phe Glu # 270 - Asp Trp Leu Pro Glu Phe Pro Glu Trp Ala Ar - #g Glu Trp Leu Lys Leu # 285 - Asp Pro Lys Arg Ser Gly Lys Tyr His Val Ty - #r Asp Pro Leu Ala Leu # 300 - Asp Leu Asp Gly Asp Gly Ile Glu Thr Val Al - #a Ala Lys Gly Phe Ala 305 3 - #10 3 - #15 3 - #20 - Gly Ala Leu Phe Asp His Arg Asn Gln Gly Il - #e Arg Thr Ala Thr Gly # 335 - Trp Val Ser Ala Asp Asp Gly Leu Leu Val Ar - #g Asp Leu Asn Gly Asn # 350 - Gly Ile Ile Asp Asn Gly Ala Glu Leu Phe Gl - #y Asp Asn Thr Lys Leu # 365 - Ala Asp Gly Ser Phe Ala Lys His Gly Tyr Al - #a Ala Leu Ala Glu Leu # 380 - Asp Ser Asn Gly Asp Asn Ile Ile Asn Ala Al - #a Asp Ala Ala Phe Gln 385 3 - #90 3 - #95 4 - #00 - Thr Leu Arg Val Trp Gln Asp Leu Asn Gln As - #p Gly Ile Ser Gln Ala # 415 - Asn Glu Leu Arg Thr Leu Glu Glu Leu Gly Il - #e Gln Ser Leu Asp Leu # 430 - Ala Tyr Lys Asp Val Asn Lys Asn Leu Gly As - #n Gly Asn Thr Leu Ala # 445 - Gln Gln Gly Ser Tyr Thr Lys Thr Asp Gly Th - #r Thr Ala Lys Met Gly # 460 - Asp Leu Leu Leu Ala Ala Asp Asn Leu His Se - #r Arg Phe Lys Asp Lys 465 4 - #70 4 - #75 4 - #80 - Val Glu Leu Thr Ala Glu Gln Ala Lys Ala Al - #a Asn Leu Ala Gly Ile # 495 - Gly Arg Leu Arg Asp Leu Arg Glu Ala Ala Al - #a Leu Ser Gly Asp Leu # 510 - Ala Asn Met Leu Lys Ala Tyr Ser Ala Ala Gl - #u Thr Lys Glu Ala Gln # 525 - Leu Ala Leu Leu Asp Asn Leu Ile His Lys Tr - #p Ala Glu Thr Asp Ser # 540 - Asn Trp Gly Lys Lys Ser Pro Met Arg Leu Se - #r Thr Asp Trp Thr Gln 545 5 - #50 5 - #55 5 - #60 - Thr Ala Asn Glu Gly Ile Ala Leu Thr Pro Se - #r Gln Val Ala Gln Leu # 575 - Lys Lys Asn Ala Leu Val Ser Leu Ser Asp Ly - #s Ala Lys Ala Ala Ile # 590 - Asp Ala Ala Arg Asp Arg Ile Ala Val Leu As - #p Ala Tyr Thr Gly Gln # 605 - Asp Ser Ser Thr Leu Tyr Tyr Met Ser Glu Gl - #u Asp Ala Leu Asn Ile # 620 - Val Lys Val Thr Asn Asp Thr Tyr Asp His Le - #u Ala Lys Asn Ile Tyr 625 6 - #30 6 - #35 6 - #40 - Gln Asn Leu Leu Phe Gln Thr Arg Leu Gln Pr - #o Tyr Leu Asn Gln Ile # 655 - Ser Phe Lys Met Glu Asn Asp Thr Phe Thr Le - #u Asp Phe Ser Gly Leu # 670 - Val Gln Ala Phe Asn His Val Lys Glu Thr As - #n Pro Gln Lys Ala Phe # 685 - Val Asp Leu Ala Glu Met Leu Ala Tyr Gly Gl - #u Leu Arg Ser Trp Tyr # 700 - Glu Gly Arg Arg Leu Met Ala Asp Tyr Val Gl - #u Glu Ala Lys Lys Ala 705 7 - #10 7 - #15 7 - #20 - Gly Lys Phe Glu Asp Tyr Gln Lys Val Leu Gl - #y Gln Glu Thr Val Ala # 735 - Leu Leu Ala Lys Thr Ser Gly Thr Gln Ala As - #p Asp Ile Leu Gln Asn # 750 - Val Gly Phe Gly His Asn Lys Asn Val Ser Le - #u Tyr Gly Asn Asp Gly # 765 - Asn Asp Thr Leu Ile Gly Gly Ala Gly Asn As - #p Tyr Leu Glu Gly Gly # 780 - Ser Gly Ser Asp Thr Tyr Val Phe Gly Lys Gl - #y Phe Gly Gln Asp Thr 785 7 - #90 7 - #95 8 - #00 - Val Tyr Asn Tyr Asp Tyr Ala Thr Gly Arg Ly - #s Asp Ile Ile Arg Phe # 815 - Thr Asp Gly Ile Thr Ala Asp Met Leu Thr Ph - #e Thr Arg Glu Gly Asn # 830 - His Leu Leu Ile Lys Ala Lys Asp Asp Ser Gl - #y Gln Val Thr Val Gln # 845 - Ser Tyr Phe Gln Asn Asp Gly Ser Gly Ala Ty - #r Arg Ile Asp Glu Ile # 860 - His Phe Asp Asn Gly Lys Val Leu Asp Val Al - #a Thr Val Lys Glu Leu 865 8 - #70 8 - #75 8 - #80 - Val Gln Gln Ser Thr Asp Gly Ser Asp Arg Le - #u Tyr Ala Tyr Gln Ser # 895 - Gly Ser Thr Leu Asn Gly Gly Leu Gly Asp As - #p Tyr Leu Tyr Gly Ala # 910 - Asp Gly Asn Asp Leu Leu Asn Gly Asp Ala Gl - #y Asn Asp Ser Ile Tyr # 925 - Ser Gly Asn Gly Asn Asp Thr Leu Asp Gly Gl - #y Glu Gly Asn Asp Ala # 940 - Leu Tyr Gly Tyr Asn Gly Asn Asp Ala Leu As - #n Gly Gly Glu Gly Asn 945 9 - #50 9 - #55 9 - #60 - Asp His Leu Asn Gly Glu Asp Gly Asn Asp Th - #r Leu Ile Gly Gly Ala # 975 - Gly Asn Asp Tyr Leu Glu Gly Gly Ser Gly Se - #r Asp Thr Tyr Val Phe # 990 - Gly Glu Gly Phe Gly Gln Asp Thr Val Tyr As - #n Tyr His Val Asp Lys # 10050 - Asn Ser Asp Thr Met His Phe Lys Gly Phe Ly - #s Ala Ala Asp Val His # 10205 - Phe Ile Arg Ser Gly Ser Asp Leu Val Leu Se - #r Ala Ser Glu Gln Asp # 10401030 - # 1035 - Asn Val Arg Ile Ser Gly Phe Phe Tyr Gly Gl - #u Asn His Arg Val Asp # 10550 - Thr Phe Val Phe Asp Asp Ala Ala Ile Ser As - #n Pro Asp Phe Ala Lys # 10705 - Tyr Ile Asn Ala Gly Asn Asn Leu Val Gln Se - #r Met Ser Val Phe Gly # 10850 - Ser Asn Thr Ala Ala Thr Gly Gly Asn Val As - #p Ala Asn Ile Gln Ser # 11005 - Val Gln Gln Pro Leu Leu Val Thr Pro Ser Al - #a 1105 1110 - # 1115 __________________________________________________________________________